Liver metastases (LM) are cancerous tumors that have metastasized from another part of the body to the liver. Most cases of liver metastases develop from colon or rectal cancers, with approximately 60 to 70 percent of people with colorectal cancer eventually developing a liver tumor. Liver metastases are a significant cause of morbidity and mortality in patients with gastrointestinal adenocarcinoma. While hepatic resection has been considered the standard of care for patients who have resectable hepatic metastases, many patients are not candidates for resection of liver metastases. Chemotherapy is not curative for liver metastases, creating a large unmet clinical need.
Tumor infiltrating lymphocyte (TIL) studies have revealed that host T cell responses to LM are significant correlates of patient survival (Katz et al., 2013, Ann Surg Oncol, 20:946-955; Katz et al., 2010, HPB (Oxford), 12:674-683; Katz et al., Ann Surg Oncol, 16:2524-2530; Wagner et al., 2008, Ann Surg Oncol, 15:2310-2317; Turcotte et al., Canc Immunol Res, 2:530-537). While those who mount effective immune responses to LM tend to have prolonged survival, the vast majority of patients succumb to their disease in the context of endogenous immune failure. The immunosuppressive nature of the intrahepatic milieu (Cantor et al., 1967, Nature, 215:744-745; Katz et al., 2005, Hepatol, 42:293-300; Katz et al., 2004, J Immunol, 173:230-235; Katz et al., 2011, J Immunol, 187:1150-1156) may promote the development of LM and contribute to aggressive disease biology.
Accordingly, there is a need for therapeutic strategies which can facilitate host or provide immunological responses to the presence of liver metastases. Given the favorable effects of robust liver TIL responses and the inherent suppressive nature of the intrahepatic space, delivery of highly specific immunoresponsive cells for the treatment of LM is a rational approach. Described herein are compositions and methods for hepatic artery infusion (HAI) of anti-CEA CAR-Ts which can both limit extrahepatic toxicity and optimize efficacy for treatment of liver metastases.